Sickled erythrocytes dramatically affect blood flow because they are relatively stiff, and they stick to each other and to the vessel wall. Thus, there is a tendency for blood flow to be sluggish or stagnant (at least transiently) in some regions of the microvasculature of sickle cell patients. This is a precarious situation, because slight changes in physiology (e.g. oxygen demand during exercise, high altitude) can catalyze a "painful crisis" in which low oxygen levels encourage cell sickling which further increases flow resistance;this self-propagating cycle results in occlusion of vascular beds with sickled cells. Unfortunately, many mechanisms contribute to the abnormal rheology of blood in sickle cell disease (SCD), and it is not clear which are the most promising targets for therapy. Because of the complexities of the fluid dynamics, this problem must be addressed from a comprehensive, systems biology perspective to improve present treatments, which are severely limited. The goal of this project is to use novel, analytical approaches to determine the best targets for 1) preventing the formation of microvascular blockages and 2) reversing asymptomatic, yet potentially dangerous, micro-occlusions that arise in SCD patients. We will use novel microfluidic devices and sophisticated mathematical simulations to assess the effects of common treatments: specifically, we will examine the effects of modulating RBC aggregation, RBC-endothelium adhesion, sickling kinetics and oxygen delivery on occlusion formation and reversal. When completed, this study will provide a formal framework for understanding and overcoming rheological aberrations in sickle cell disease.